title: Growth of chronic myeloid leukemia cells is inhibited by infection with Ad-SH2-HA adenovirus that disrupts Grb2-Bcr-Abl complexes.
abstract: The persistence of Bcr-Abl-positive cells in patients on imatinib therapy indicates that inhibition of the Bcr-Abl kinase activity alone might not be sufficient to eradicate the leukemia cells. Many downstream effectors of Bcr-Abl have been described, including activation of both the Grb2-SoS-Ras-MAPK and Grb2-Gab2-PI3K-Akt pathways. The Bcr-Abl-Grb2 interaction, which is mediated by the direct interaction of the Grb2 SH2 domain with the phospho-Bcr-Abl Y177, is required for activation of these signaling pathways. Therefore, disrupting their interaction represents a potential therapeutic strategy for inhibiting the oncogenic downstream signals of Bcr-Abl. Adenovirus Ad-SH2-HA expressing the Grb2 SH2 domain was constructed and applied in this study. As expected, Ad-SH2-HA efficiently infected CML cells and functioned by binding to the phospho-Bcr-Abl Y177 site, competitively disrupting the Grb2 SH2-phospho-Bcr-Abl Y177 complex. They induced potent anti-proliferation and apoptosis-inducing effects in CML cell lines. Moreover, the Ras, MAPK and Akt activities were significantly reduced in the Ad-SH2-HA treated cells. These were not observed with the point-mutated control adenovirus Ad-Sm-HA with abolished phospho-Bcr-Abl Y177 binding sites. These data indicate that, in addition to the direct targeting of Bcr-Abl, selective inhibition of its downstream signaling pathways may be a therapeutic option for CML, and the Ad-SH2-HA-mediated killing strategy could be explored as a promising anti-leukemia agent in CML.
authors.affiliation: Department of Clinical Hematology, Key Laboratory of Laboratory Medical Diagnostics Designated by the Ministry of Education, Chongqing Medical University, and Clinical Laboratory and Hematology, the First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, PR China.
authors.forename: Zhi
authors.initials: Z
authors.lastname: Peng
authors.forename: Hong-Wei
authors.initials: HW
authors.lastname: Luo
authors.forename: Ying
authors.initials: Y
authors.lastname: Yuan
authors.forename: Jing
authors.initials: J
authors.lastname: Shi
authors.forename: Shi-Feng
authors.initials: SF
authors.lastname: Huang
authors.forename: Chun-Li
authors.initials: CL
authors.lastname: Li
authors.forename: Wei-Xi
authors.initials: WX
authors.lastname: Cao
authors.forename: Zong-Gan
authors.initials: ZG
authors.lastname: Huang
authors.forename: Wen-Li
authors.initials: WL
authors.lastname: Feng
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D017209:Apoptosis / Q000235:genetics; D001665:Binding Sites; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004789:Enzyme Activation; D016044:Fusion Proteins, bcr-abl / Q000378:metabolism*; D051380:GRB2 Adaptor Protein / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D023061:Gene Order; D005822:Genetic Vectors / Q000235:genetics; D057809:HEK293 Cells; D018922:HL-60 Cells; D006801:Humans; D020014:K562 Cells; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000378:metabolism / Q000473:pathology*; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D011485:Protein Binding; D021381:Protein Transport; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras) / Q000378:metabolism; D018909:src Homology Domains / Q000235:genetics*
chemical_list: D051380:GRB2 Adaptor Protein; D016044:Fusion Proteins, bcr-abl; D051057:Proto-Oncogene Proteins c-akt; D020929:Mitogen-Activated Protein Kinase Kinases; D016283:Proto-Oncogene Proteins p21(ras)